[ESC guidelines 2019 on diagnostics and management of acute pulmonary embolism]. / ESC-Leitlinien 2019 zu Diagnostik und Management der akuten Lungenembolie.

This article on the new European Society of Cardiology (ESC) guidelines for diagnostics and management of acute pulmonary embolism (PE) focusses on new or changed recommendations compared to the previous version of the guidelines from 2014. The current risk-adjusted management algorithm for acute PE includes the clinical severity, aggravating comorbid conditions and right ventricular dysfunction. For low-risk patients early discharge and outpatient treatment are possible, whereas for high-risk patients reperfusion treatment and hemodynamic support have to be considered, depending on the hemodynamic situation and contraindications in the individual patient. Effective therapeutic anticoagulation for at least 3 months is recommended for all patients with PE. Potential indicators for extended anticoagulation are given in the guidelines (class I or class IIa recommendations). New oral anticoagulants (NOAC) are the first choice for anticoagulation in preference to vitamin K antagonists (VKA); however, they are not recommended in patients with severe renal dysfunction, during pregnancy or lactation and in patients with antiphospholipid antibody syndrome. Furthermore, a new algorithm for the follow-up after acute PE is proposed in the guidelines. In cases of symptomatic persistent pulmonary hypertension (PH) the transfer to a specialized center is recommended.

Sex-based differences in outcomes with bivalirudin or unfractionated heparin for transcatheter aortic valve replacement: Results from the BRAVO-3 randomized trial.

BACKGROUND: Women comprise almost 50% of patients undergoing transcatheter aortic valve replacement (TAVR) and previous studies have indicated higher rates of procedural complications and bleeding in women compared to men. It is unknown whether men and women demonstrate a differential response to bivalirudin versus unfractionated heparin (UFH) in TAVR. We sought to evaluate outcomes by sex and type of anticoagulant from the Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement (BRAVO-3) trial of transfemoral TAVR. METHODS: BRAVO-3 was a randomized multicenter trial comparing transfemoral TAVR with bivalirudin versus UFH (31 centers, n = 802). The primary endpoint was 48 h major bleeding defined as Bleeding Academic Research Consortium (BARC) type ≥3b. Major adverse cardiovascular events (MACE) were a composite of 30-day death, myocardial infarction, or stroke. Net adverse cardiovascular events (NACE) were a composite of BARC ≥3b bleeding or 30-day MACE. We examined the outcomes in men and women. RESULTS: The total cohort included 49% women (n = 391, 195 received bivalirudin and 196 UFH) and 51% men (n = 411, 209 received bivalirudin and 202 UFH). Women were older than men with fewer comorbidities including coronary artery disease, atrial fibrillation, diabetes but similar EuroSCORE I. Women received smaller sheath and device sizes compared with men without differences in the use of vascular closure devices. At 48-hr post-TAVR there was no difference in bleeding or vascular complications in women compared to men. The use of bivalirudin did not result in significantly lower bleeding at 48 hr or 30-days compared to UFH. CONCLUSIONS: There was no difference in early outcomes with bivalirudin versus UFH in men or women undergoing contemporary TAVR. © 2016 Wiley Periodicals, Inc.

Socially disadvantaged city districts show a higher incidence of acute ST-elevation myocardial infarctions with elevated cardiovascular risk factors and worse prognosis.

BACKGROUND: The importance of socioeconomic status (SES) for coronary heart disease (CHD)-morbidity is subject of ongoing scientific investigations. This study was to explore the association between SES in different city-districts of Bremen/Germany and incidence, severity, treatment modalities and prognosis for patients with ST-elevation myocardial infarctions (STEMI). METHODS: Since 2006 all STEMI-patients from the metropolitan area of Bremen are documented in the Bremen STEMI-registry. Utilizing postal codes of their home address they were assigned to four groups in accordance to the Bremen social deprivation-index (G1: high, G2: intermediate high, G3: intermediate low, G4: low socioeconomic status). RESULTS: Three thousand four hundred sixty-two consecutive patients with STEMI admitted between 2006 and 2015 entered analysis. City areas with low SES showed higher adjusted STEMI-incidence-rates (IR-ratio 1.56, G4 vs. G1). This elevation could be observed in both sexes (women IRR 1.63, men IRR 1.54) and was most prominent in inhabitants <50 yrs. of age (women IRR 2.18, men IRR 2.17). Smoking (OR 1.7, 95%CI 1.3-2.4) and obesity (1.6, 95%CI 1.1-2.2) was more prevalent in pts. from low SES city-areas. While treatment-modalities did not differ, low SES was associated with more extensive STEMIs (creatine kinase > 3000 U/l, OR 1.95, 95% CI 1.4-2.8) and severe impairment of LV-function post-STEMI (OR 2.0, 95% CI 1.2-3.4). Long term follow-up revealed that lower SES was associated with higher major adverse cardiac or cerebrovascular event (MACCE)-rates after 5 years: G1 30.8%, G2 35.7%, G3 36.0%, G4 41.1%, p (for trend) = 0.02. This worse prognosis could especially be shown for young STEMI-patients (<50 yrs. of age) 5-yr. mortality-rates(G4 vs. G1) 18.4 vs. 3.1%, p = 0.03 and 5-year-MACCE-rates (G4 vs. G1) 32 vs. 6.3%, p = 0.02. CONCLUSIONS: This registry-data confirms the negative association of low socioeconomic status and STEMI-incidence, with higher rates of smoking and obesity, more extensive infarctions and worse prognosis for the socio-economically deprived.

[Differential therapy in coronary heart disease]. / Differenzialtherapie der koronaren Herzkrankheit.

The various contemporary therapeutic options for coronary artery disease (CAD) require differentiated, individualized treatment strategies. The foundations of CAD therapy are lifestyle modifications targeted on the individual risk profile of the patients. Pharmacological therapy of CAD should prevent secondary coronary events (e.g. platelet aggregation inhibitors and statins) and reduce angina in symptomatic patients (e.g. short-acting nitrates, beta blockers, calcium channel blockers and if necessary ivabradine and ranolazine). Revascularization therapy has to be performed promptly in patients with acute coronary syndromes; however, in patients with stable CAD the decision to perform revascularization therapy has to consider symptoms, detection of ischemia and if appropriate intracoronary assessment of hemodynamic relevance of an intermediate stenosis (fractional flow reserve). The differential indications of percutaneous coronary intervention compared to coronary artery bypass grafting depend on the severity of coronary artery disease and the morphology (SYNTAX score), comorbidities and the will of the individual patient. The international guidelines emphasize the value of an interdisciplinary treatment decision in a "heart team". In summary, differential therapy of CAD has become challenging in the current clinical practice; future developments will probably further improve individualized strategies to treat patients with CAD.

Impact of coronary artery disease on in-hospital mortality in patients with aortic valve disease. Results from the German ALKK registry.

OBJECTIVE: Although aortic valve disease (AVD) is frequently associated with coronary artery disease (CAD), little is known about the impact of significant coronary artery disease on mortality after diagnostic cardiac catheterization in patients with AVD. METHODS: We analyzed data of the coronary angiography registry of the "Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte" (ALKK) in Germany. The primary endpoint was in-hospital mortality. RESULTS: A total of 1427 consecutive patients with AVD (438 patients with CAD versus 989 patients without CAD) underwent diagnostic catheterization in 2006 in 42 hospitals. All cause in-hospital mortality was more than threefold higher in patients with CAD (16/438; 3.7%) as compared to patients without CAD (12/989; 1.2%; p < 0.01; OR 3.09, 95% CI 1.45-6.58). Even after adjustment for age, sex, presence of diabetes mellitus and renal insufficiency, in-hospital all cause mortality remained statistically significant different between the two groups (OR 2.4; 95% CI 1.09-5.28; p < 0.01). Several factors, such as transient ischemic attack/stroke, volume of contrast agent, and left heart catheter-associated complications could not be identified as possible causes for the increase in mortality. CONCLUSION: This analysis in patients with the leading diagnosis of AVD shows a significantly higher in-hospital mortality after diagnostic cardiac catheterization in case of an accompanying CAD. However, further studies are necessary to identify the driving force for the increase in mortality.

[Physical exercise training for cardiovascular diseases]. / Trainingstherapie bei kardiologischen Patienten (Sportkardiologie).

Clinical application of physical exercise has developed into an evidence-based therapeutic option for cardiovascular diseases, especially coronary artery disease (CAD) and chronic heart failure (CHF). In CAD regular physical exercise training partially corrects endothelial dysfunction and leads to an economization of left ventricular function. Meta-analyses have shown a reduction of angina pectoris symptoms and a decrease of total and cardiovascular mortality by regular aerobic exercise training. Endurance training for CHF reduces cardiac afterload by correcting peripheral endothelial dysfunction und leads to a better left ventricular function. In addition exercise training reduces the adrenergic tone and the stimulation of the renin-angiotensin-aldosterone system in CHF. Exercise training provides positive effects on the metabolism and function of skeletal muscle (e.g. reduced inflammation and oxidative stress). Supervised regular physical exercise training in CHF is safe and has improved the morbidity in clinical studies. Thus aerobic exercise training is an important component of therapeutic management of stable CAD and CHF with a class 1a recommendation in the current guidelines.

Interdisciplinary consensus on indications for transfemoral transcatheter aortic valve implantation (TF-TAVI) : Joint Consensus Document of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte e.V. (ALKK) and cooperating Cardiac Surgery Departments.

Indications for TF-TAVI (transfemoral transcatheter aortic valve implantation) are rapidly changing according to increasing evidence from randomized controlled trials. Present trials document the non-inferiority or even superiority of TF-TAVI in intermediate-risk patients (STS-Score 4-8%) as well as in low-risk patients (STS-Score < 4%). However, risk scores exhibit limitations and, as a single criterion, are unable to establish an appropriate indication of TF-TAVI vs transapical TAVI vs SAVR (surgical aortic valve replacement). The ESC (European Society of Cardiology)/EACTS (European Association for Cardio-Thoracic Surgery) guidelines 2017 and the German DGK (Deutsche Gesellschaft für Kardiologie)/DGTHG (Deutsche Gesellschaft für Thorax-, Herz- und Gefäßchirurgie) commentary 2018 offer a framework for the selection of the best therapeutic method, but the individual decision is left to the discretion of the heart teams. An interdisciplinary TAVI consensus group of interventional cardiologists of the ALKK (Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte e.V.) and cardiac surgeons has developed a detailed consensus on the indications for TF-TAVI to provide an up-to-date, evidence-based, comprehensive decision matrix for daily practice. The matrix of indication criteria includes age, risk scores, contraindications against SAVR (e.g., porcelain aorta), cardiovascular criteria pro TAVI, additional criteria pro TAVI (e.g., frailty, comorbidities, organ dysfunction), contraindications against TAVI (e.g., endocarditis) and cardiovascular criteria pro SAVR (e.g., bicuspid valve anatomy). This interdisciplinary consensus may provide orientation to heart teams for individual TAVI-indication decisions. Future adaptations according to evolving medical evidence are to be expected. Interdisciplinary consensus on indications for transfemoral transcatheter aortic valve implantation (TF-TAVI).

Exercise training in coronary artery disease and coronary vasomotion.

Exercise training has assumed a major role in cardiac rehabilitation, mostly because of its positive effects on myocardial perfusion in patients with coronary artery disease. The mechanisms involved in mediating this key effect have long been debated: both regression of coronary artery stenosis and improvement of collateralization have been suggested as potential adaptations. However, the comparatively minute changes in luminal diameter and myocardial contrast staining do not fully explain the significant changes in myocardial perfusion. During the last decade, endothelial dysfunction was identified as a trigger of myocardial ischemia. The impaired production of endothelium-derived nitric oxide (NO) in response to acetylcholine and flow leads to paradoxic vasoconstriction and exercise-induced ischemia. Recently, it was confirmed in humans that training attenuates paradoxic vasoconstriction in coronary artery disease and increases coronary blood flow in response to acetylcholine. Data from cell-culture and animal experiments suggest that shear stress acts as a stimulus for the endothelium to increase the transport capacity for L-arginine (the precursor molecule for NO), to enhance NO synthase activity and expression, and to increase the production of extracellular superoxide dismutase, which prevents premature breakdown of NO. Exercise also affects the microcirculation, where it sensitizes resistance arteries for the vasodilatory effects of adenosine. These novel findings provide a pathophysiological framework to explain the improvement of myocardial perfusion in the absence of changes in baseline coronary artery diameter. Because endothelial dysfunction has been identified as a predictor of coronary events, exercise may contribute to the long-term reduction of cardiovascular morbidity and mortality.

Reversal of cardiogenic shock by percutaneous left atrial-to-femoral arterial bypass assistance.

BACKGROUND: Recovery of myocardial function after revascularization of acutely occluded coronary arteries may require several days. During this critical time, patients in cardiogenic shock may have low output. A newly developed percutaneous left ventricular assist device (VAD) may offer effective treatment for these patients by providing active circulatory support. METHODS AND RESULTS: Between May 2000 and May 2001, VADs were implanted in 18 consecutive patients who had cardiogenic shock after myocardial infarction. The device was connected to the patient's circulation by insertion of a 21F venous cannula into the left atrium by transseptal puncture; blood was returned to the iliac artery through an arterial cannula. Mean duration of cardiac assistance was 4+/-3 days. Mean flow of the VAD was 3.2+/-0.6 L/min. Before support, cardiac index was 1.7+/-0.3 L/min per m(2) and improved to 2.4+/-0.6 L/min per m(2) (P<0.001). Mean blood pressure increased from 63+/-8 mm Hg to 80+/-9 mm Hg (P<0.001). Pulmonary capillary wedge pressure, central venous pressure, and pulmonary artery pressure were reduced from 21+/-4, 13+/-4, and 31+/-8 mm Hg to 14+/-4, 9+/-3, and 23+/-6 mm Hg (all P<0.001), respectively. Overall 30-day mortality rate was 44%. CONCLUSIONS: A newly developed VAD can be rapidly deployed in the catheterization laboratory setting. This device provides up to 4.0 L/min of assisted cardiac output, which may aid to revert cardiogenic shock. The left ventricle is unloaded by diverting blood from the left atrium to the systemic circulation, making recovery more likely after an ischemic event. The influence of this device on long-term prognosis warrants further investigation.

Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase.

BACKGROUND: In stable coronary artery disease (CAD), exercise training has well-documented positive effects on arterial endothelial function. NO derived from endothelial NO synthase (eNOS) is regarded as a protective factor against atherosclerosis. The aim of the present study was to investigate the effects of exercise training on the endothelial function in relation to the expression of eNOS and Akt-dependent eNOS phosphorylation in the left internal mammary artery (LIMA) of patients with stable CAD. METHODS AND RESULTS: In 17 training patients (T) and 18 control patients (C), endothelium-dependent vasodilation and average peak flow velocity (APV) in response to acetylcholine were measured invasively at study beginning and after 4 weeks in the LIMA. In LIMA tissue sampled during bypass surgery, eNOS expression and content of pospho-eNOS-Ser1177, Akt, and phospho-Akt were determined by Western blot and quantitative reverse transcriptase-polymerase chain reaction. After exercise training, LIMA APV in response to acetylcholine was increased by 56+/-8% (from +48+/-8% at beginning to +104+/-11% after 4 weeks, P<0.001). Patients in T had a 2-fold higher eNOS protein expression (T 1.0+/-0.7 versus C 0.5+/-0.3 arbitrary units, P<0.05) and 4-fold higher eNOS Ser1177-phosphorylation levels in LIMA-endothelium (1.2+/-0.9 versus 0.3+/-0.2 arbitrary units, P<0.01). A linear correlation was confirmed between Akt phosphorylation and phospho-eNOS levels (R=0.80, P<0.05) and between phospho-eNOS and Delta APV (R=0.59, P<0.05). CONCLUSIONS: Exercise training in stable CAD leads to an improved agonist-mediated endothelium-dependent vasodilatory capacity. The change in acetylcholine-induced vasodilatation was closely related to a shear stress-induced/Akt-dependent phosphorylation of eNOS on Ser1177.

Endothelial dysfunction in patients with chronic heart failure: systemic effects of lower-limb exercise training.

OBJECTIVES: We sought to analyze the systemic effects of lower-limb exercise training (ET) on radial artery endothelial function in patients with chronic heart failure (CHF). BACKGROUND: Local ET has the potential to improve local endothelial dysfunction in patients with CHF. However, it remains unclear whether the systemic effects can be achieved by local ET. METHODS: Twenty-two male patients with CHF were prospectively randomized to either ET on a bicycle ergometer (ET group, n = 11; left ventricular ejection fraction [LVEF] 26 +/- 3%) or an inactive control group (group C, n = 11; LVEF 24 +/- 2%). At the beginning of the study and after four weeks, endothelium-dependent and -independent vasodilation of the radial artery was determined by intra-arterial infusion of acetylcholine (ACh-7.5, 15 and 30 microg/min) and nitroglycerin (0.2 mg/min). The mean internal diameter (ID) of the radial artery was assessed using a high resolution ultrasound system (NIUS-02, Asulab Research Laboratories, Neuchâtel, Switzerland) with a 10-MHz probe. RESULTS: After four weeks of ET, patients showed a significant increase in the baseline-corrected mean ID in response to ACh (30 microg/min), from 33 +/- 10 to 127 +/- 25 microm (p < 0.001 vs. control group at four weeks). In the control group, the response to ACh (30 microg/min) remained unchanged. Endothelium-independent vasodilation was similar in both groups at the beginning of the study and at four weeks. In the training group, increases in agonist-mediated, endothelium-dependent vasodilation correlated to changes in functional work capacity (r = 0.63, p < 0.05). CONCLUSIONS: In patients with stable CHF, bicycle ergometer ET leads to a correction of endothelial dysfunction of the upper extremity, indicating a systemic effect of local ET on endothelial function.

Myocardial perfusion and regression of coronary artery disease in patients on a regimen of intensive physical exercise and low fat diet.

This intervention program tested the applicability and effects of intensive physical exercise and a low fat diet on progression of coronary atherosclerotic lesions and stress-induced myocardial ischemia in patients with stable angina pectoris. Eighteen patients participated in this program for 1 year; they consumed a low fat, low cholesterol diet (less than 20 energy % fat, cholesterol less than 200 mg/day) and exercised for greater than 3 h/week. Change in coronary morphology was assessed by angiography and digital image processing; stress-induced myocardial ischemia was measured by thallium-201 scintigraphy. Results were compared with those in patients receiving "usual care." In the intervention group, significant regression of coronary atherosclerotic lesions was noted in 7 of the 18 patients; no change or progression was present in 11 patients. In patients receiving usual care, regression was detected in only 1, with no change or progression in 11 patients (different from intervention, p less than 0.05). There was a significant reduction in stress-induced myocardial ischemia, which was not limited to patients with regression of coronary atherosclerotic lesions. Thus, regular physical exercise and a low fat diet may retard progression of coronary artery disease; however, improvement of myocardial perfusion may be achieved independently from regression of stenotic lesions.

Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation.

OBJECTIVES: The aim of this study was to analyze whether L-arginine (L-arg.) has comparable or additive effects to physical exercise regarding endothelium-dependent vasodilation in patients with chronic heart failure (CHF). BACKGROUND: Endothelial dysfunction in patients with CHF can be corrected by both dietary supplementation with L-arg. and regular physical exercise. METHODS: Forty patients with severe CHF (left ventricular ejection fraction 19 +/- 9%) were randomized to an L-arg. group (8 g/day), a training group (T) with daily handgrip training, L-arg. and T (L-arg. + T) or an inactive control group (C). The mean internal radial artery diameter was determined at the beginning and after four weeks in response to brachial arterial administration of acetylcholine (ACh) (7.5, 15, 30 microg/min) and nitroglycerin (0.2 mg/min) with a transcutaneous high-resolution 10 MHz A-mode echo tracking system coupled with a Doppler device. The power of the study to detect clinically significant differences in endothelium-dependent vasodilation was 96.6%. RESULTS: At the beginning, the mean endothelium-dependent vasodilation in response to ACh, 30 microg/min was 2.54 +/- 0.09% (p = NS between groups). After four weeks, internal radial artery diameter increased by 8.8 +/- 0.9% after ACh 30 microg/min in L-arg. (p < 0.001 vs. C), by 8.6 +/- 0.9% in T (p < 0.001 vs. C) and by 12.0 +/- 0.3% in L-arg. +/- T (p < 0.005 vs. C, L-arg. and T). Endothelium-independent vasodilation as assessed by infusion of nitroglycerin was similar in all groups at the beginning and at the end of the study. CONCLUSIONS: Dietary supplementation of L-arg. as well as regular physical exercise improved agonist-mediated, endothelium-dependent vasodilation to a similar extent. Both interventions together seem to produce additive effects with respect to endothelium-dependent vasodilation.

Various intensities of leisure time physical activity in patients with coronary artery disease: effects on cardiorespiratory fitness and progression of coronary atherosclerotic lesions.

OBJECTIVES: This study was designed to define the effect of different levels of leisure time physical activity on cardiorespiratory fitness and progression of coronary atherosclerotic lesions in unselected patients with coronary artery disease. BACKGROUND: It has been shown in various studies that regression of coronary atherosclerotic lesions can be achieved by means of lipid-lowering drugs, reduction of fat consumption and physical exercise. METHODS: Patients were prospectively randomized either to an intervention group (n = 29) participating in regular physical exercise or to a control group (n = 33) receiving usual care. Energy expenditure in leisure time physical activity was estimated from standardized questionnaires and from participation in group exercise sessions. After 12 months of participation, repeat coronary angiography was performed; coronary lesions were measured by digital image processing. RESULTS: After 1 year, patients in the intervention group achieved an increase in oxygen uptake at a ventilatory threshold of 7% (p < 0.001) and peak exercise of 14% (p < 0.05), whereas a significant decrease was observed in patients in the control group. To achieve significant improvement in cardiorespiratory fitness, approximately 1,400 kcal/week had to be expended in the form of leisure time physical activity (p < 0.001). The mean energy expended in such activity was 1,876 +/- 163 kcal/week in the intervention group and 1,187 +/- 97 kcal/week in the control group (p < 0.001). In the intervention group, regression of coronary artery disease was noted in 8 patients (28%), progression of disease in 3 (10%) and no change in coronary morphology in 18 (62%). In contrast, coronary artery disease progressed at a significantly faster rate in patients in the control group (progression in 45%, no change in 49% and regression in 6%) (p < 0.001 vs. intervention). When the two groups were combined, the lowest level of leisure time physical activity was noted in patients with progression of disease (1,022 +/- 142 kcal/week) as opposed to patients with no change (1,533 +/- 122 kcal/week) or regression of disease (2,204 +/- 237 kcal/week) (p < 0.005). CONCLUSIONS: Measurable improvement in cardiorespiratory fitness requires approximately 1,400 kcal/week of leisure time physical activity; higher work loads are necessary to halt progression of coronary atherosclerotic lesions (1,533 +/- 122 kcal/week), whereas regression of coronary lesions is observed only in patients expending an average of 2,200 kcal/week in leisure time physical activity, amounting to approximately 5 to 6 h/week of regular physical exercise.

Exercise intolerance in patients with chronic heart failure and increased expression of inducible nitric oxide synthase in the skeletal muscle.

OBJECTIVES: This study was designed to analyze the effect of iNOS on mitochondrial creatine kinase (mi-CK) expression and exercise capacity in chronic heart failure (CHF). BACKGROUND: The molecular mechanisms underlying exercise intolerance in CHF are still unclear. Expression of inducible nitric oxide synthase (iNOS) and reduced phosphocreatine resynthesis have been described in skeletal muscle of patients with CHF. However, it is unknown whether these phenomena are causally related to each other and to exercise tolerance. METHODS: Thirty-eight patients with CHF and 8 healthy controls (C) underwent bicycle ergospirometry and biopsy of the vastus lateralis muscle. Expression of iNOS was quantified by immunohistochemistry and reverse-transcriptase polymerase chain reaction, mi-CK by Western-blot. Intracellular presence of NO was confirmed by immunohistochemical quantification of nitrotyrosine (NT). To corroborate clinical findings, L6 rat skeletal myoblasts were incubated with sodium nitroprusside (SNP). RESULTS: Expression of iNOS was significantly increased in CHF (4.0+/-2.8 vs. 0.8+/-0.7% iNOS positive tissue area, p < 0.001 vs. C) and inversely correlated to maximal oxygen uptake (r=-0.65, p < 0.001). Intracellular NO-accumulation was confirmed by increased NT levels (13.5+/-8.5 vs. 2.0+/-1.7% NT-positive tissue area, p < 0.001 vs. C). Mi-CK was decreased in CHF (0.84+/-0.36 vs. 1.57+/-0.60, p < 0.001 vs. C). The inverse correlation seen between iNOS and mi-CK expression in patients (r=-0.68, p < 0.001) was reproduced in incubation experiments with SNP. CONCLUSIONS: Increased expression of iNOS in skeletal muscle of patients with CHF was inversely correlated with mi-CK expression and exercise capacity. Cell experiments confirmed a causal relationship via NO. These findings extend our knowledge of the pathophysiology of exercise intolerance in CHF.

Apoptosis in skeletal myocytes of patients with chronic heart failure is associated with exercise intolerance.

OBJECTIVES: The purpose of the study was to investigate if apoptosis occurs in skeletal muscle myocytes and its relation to exercise intolerance in patients with chronic heart failure (CHF). BACKGROUND: Intrinsic abnormalities of skeletal muscle frequently limit exercise tolerance in CHF patients. Recently, apoptosis has been detected in cardiac myocytes of patients with CHF, suggesting that apoptosis may contribute to the reduced contractile force. The presence and regulation of apoptosis in skeletal myocytes of patients with CHF remains to be defined. METHODS: Skeletal muscle biopsies (m. vastus lateralis) of 34 CHF patients (New York Heart Association functional class II-III) and eight age-matched healthy control subjects were analyzed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling for the presence of apoptosis, and by immunohistochemistry and videodensitometrical quantification for inducible nitric oxide synthase (iNOS) and Bcl-2 expression. Maximal oxygen consumption (VO2max) was determined by ergospirometry. RESULTS: Apoptosis was detected in 16/34 (47%) patients with CHF and in none of the healthy subjects. Patients with apoptosis-positive skeletal muscle myocytes exhibited a significantly lower VO2max (12.0 +/- 3.7 vs. 18.2 +/- 4.4 ml/kg/min; p = 0.0005), a higher iNOS expression (6.8 +/- 3.6 vs. 3.7 +/- 2.6% iNOS-positive stained tissue area; p = 0.015) and a lower Bcl-2 expression (1.0 +/- 0.3 vs. 1.4 +/- 0.4% Bcl-2-positive tissue area; p = 0.03) as compared with patients with apoptosis-negative biopsies. CONCLUSIONS: These results indicate that apoptosis is frequently found in skeletal muscle obtained from CHF patients, which is associated with significant impairment of functional work capacity. In skeletal muscle of these patients, iNOS and Bcl-2 are possibly involved in the regulation of apoptosis.

Physical training in patients with stable chronic heart failure: effects on cardiorespiratory fitness and ultrastructural abnormalities of leg muscles.

OBJECTIVES: The present study was designed to evaluate the effect of an ambulatory training program on ultrastructural morphology and the oxidative capacity of skeletal muscle and its relation to central and peripheral hemodynamic variables in patients with chronic heart failure. BACKGROUND: Clinical evidence supports the hypothesis that exercise intolerance in patients with chronic heart failure is not only a consequence of low cardiac output, but is also a result of alterations in oxidative metabolism of skeletal muscle. METHODS: Twenty-two patients were prospectively randomized either to a training group (mean [+/-SD] ejection fraction 26 +/- 9%, n = 12) participating in an ambulatory training program or to a physically inactive control group (ejection fraction 27 +/- 10%, n = 10). At baseline and after 6 months, patients underwent symptom-limited bicycle exercise testing, and central and peripheral hemodynamic variables were measured. Percutaneous needle biopsy samples of the vastus lateralis muscle were obtained at baseline and after 6 months. The ultrastructure of skeletal muscle was analyzed by ultrastructural morphometry. RESULTS: After 6 months, patients in the training group achieved an increase in oxygen uptake at the ventilatory threshold of 23% (from 0.86 +/- 0.2 to 1.07 +/- 0.2 liters/min, p < 0.01 vs. control group) and at peak exercise of 31% (from 1.49 +/- 0.4 to 1.95 +/- 0.4 liters/min, p < 0.01 vs. control group). There was no significant change in oxygen uptake at the ventilatory threshold and at peak exercise in the control group. The total volume density of mitochondria and volume density of cytochrome c oxidase-positive mitochondria increased significantly by 19% (from 4.7 +/- 1.5 to 5.6 +/- 1.5 vol%, p < 0.05 vs. control group) and by 41% (from 2.2 +/- 1.0 to 3.1 +/- 1.0 vol%, p < 0.05 vs. control group) after 6 months of regular physical exercise. Cardiac output at rest and at submaximal exercise remained unchanged but increased during maximal symptom-limited exercise from 11.9 +/- 4.0 to 14.1 +/- 3.3 liters/min in the training group (p < 0.05 vs. baseline; p = NS vs. control group). Peak leg oxygen consumption increased significantly by 45% (from 510 +/- 172 to 740 +/- 254 ml/min, p < 0.01 vs. control group). Changes in cytochrome c oxidase-positive mitochondria were significantly related to changes in oxygen uptake at the ventilatory threshold (r = 0.82, p < 0.0001) and at peak exercise (r = 0.87, p < 0.0001). CONCLUSIONS: Regular physical training increases maximal exercise tolerance and delays anaerobic metabolism during submaximal exercise in patients with stable chronic heart failure. Improved functional capacity is closely linked to an exercise-induced increase in the oxidative capacity of skeletal muscle.

Effects of endurance training on mitochondrial ultrastructure and fiber type distribution in skeletal muscle of patients with stable chronic heart failure.

OBJECTIVES: The present study was designed to evaluate the effects of an ambulatory training program in patients with chronic heart failure (CHF) on the ultrastructural morphology of mitochondria and fiber type distribution of skeletal muscle and its relation to peripheral perfusion. BACKGROUND: Recent studies in patients with CHF have suggested that intrinsic abnormalities in skeletal muscle can contribute to the development of early lactic acidosis and fatigue during exercise. METHODS; Patients were prospectively randomized to either a training group (n = 9; mean [+/- SD] left ventricular ejection fraction [LVEF] 26 +/- 10) participating in an ambulatory training program or to a physically inactive control group (n = 9; LVEF 28 +/- 10%). At baseline and after 6 months, patients underwent symptom-limited bicycle exercise testing with measurement of central and peripheral hemodynamic variables as well as percutaneous needle biopsies of the vastus lateralis muscle. The mitochondrial ultrastructure of skeletal muscle was analyzed by ultrastructural morphometry; cytochrome c oxidase activity was visualized by histochemistry and subsequently quantitated by morphometry. The fiber type distribution was determined by adenosine triphosphatase staining. RESULTS: After 6 months of exercise training there was a significant increase of 41% in the surface density of cytochrome c oxidase-positive mitochondria (SVMOcox+) (p < 0.05 vs. control) and of 43% in the surface density of mitochondrial cristae (SVMC) (p < 0.05 vs. control). Furthermore, exercise training induced a 92% increase in the surface density of the mitochondrial inner border membrane (p < 0.05 vs. control). In contrast, the total number of cytochrome c oxidase-positive mitochondria remained essentially unchanged. Exercise-induced improvement in peak oxygen uptake was closely linked to changes in SVMOcox+ (p < 0.01, r = 0.66). After exercise training, changes in submaximal femoral venous lactate levels were not related to changes in submaximal leg blood flow (r = -0.4), but were inversely related to changes in the volume density of mitochondria (p = 0.01; r = -0.6) as well as to changes in SVMC (p < 0.05; r = -0.5). After exercise training there was a "reshift" from type II to type I fibers (p < 0.05 vs. control). CONCLUSIONS: Patients with CHF who engage in regular physical exercise show enhanced oxidative enzyme activity in the working skeletal muscle and a concomitant reshift to type I fibers. These exercise-induced changes in oxidative capacity appear to be unrelated to changes in peripheral perfusion.

[Effects of physical training of chronic cardiac insuffciency]. / Grundlegender Wandel in der Therapie der chronischen Herzinsuffizienz: Vom Sessel auf das Laufband!

During the last ten years,the traditional dogma "physical rest" for patients with chronic cardiac insufficiency (CCI) has been increasingly abandoned. Studies on the effects of low intensity physical endurance training for patients with stable CCI showed the following effects after 12 months: Decrease in the heart size and a slight improvement in the EF, reduction of the systemic vascular resistance during rest and during stress through improvement of the endothelial function, increase in the physical performance by 12 to 26%, reduction of local inflammation and improvement of the oxidative metabolism in skeletal muscles, an end to muscle atrophy and reduction of the total mortality. Training programs for patients with chronic cardiac insufficiency today represent an established auxiliary therapy for CCI with prognostic relevance.